DESCRIPTION: The goal of the proposed research is to understand the cellular, genetic, and ultimately molecular mechanism underlying nervous system control of defecation behavior in the nematode Caeorhabditis elegans. Defecation is studied because it is accomplished by the periodic activation of a motor program that is readily observed and because genetic analysis of this behavior is powerful. The primary focus is on two aspects of this behavior: motor program function and periodicity. First, three genes that are required for a GABA-activated muscle contraction will be studied molecularly. The genes will be sequenced, their gene products localized in vivo, and their expression assessed in the many other mutants that affect control of defecation muscle function. Two of these three genes, unc-43 and aex-3, are implicated in controlling activation of the motor program (rather than its execution) and their molecular identity and localization should identify neurons that control this activation step. The third gene, egl-2, is a target for tricyclic antidepressant action in C. elegans. Genetic and pharmacological evidence indicates that the egl-2 target for tricyclics is unrelated to serotonin reuptake. This fact suggests that egl-2 identifies a novel in vivo target for this important class of drugs. Molecular cloning and analysis of egl-2 will provide insight into the in vivo activities of the tricyclics. Activation of the defecation motor program is controlled by a temperature-compensated ultradian (less than 24 hour) clock. Mutations in twelve genes have been identified that either shorten or lengthen defecation periodicity. Continued genetic analysis, followed by molecular analysis of the most interesting of these genes, offer a unique opportunity to study control of a short-period biological clock. Two features of the proposed study are of general health related interest. First, C. elegans provides the only model for the systematic genetic and molecular study of defecation, a behavior nearly universal in metazoans, and in which there are a wide range of disorders in humans. Second, the in vivo actions of tricyclic antidepressants are very unclear and study of egl-2, a tricyclic antidepressant target, will provide insight into the action of this important class of psychotherapeutic drugs.